To Stave off Alzheimer’s, Stay Hungry?

A strategy summed up by a famous Nietzsche quote – “What does not destroy me makes me stronger”—might provide a drug-free method for delaying Alzheimer’s and other neurodegenerative diseases, and perhaps the aging process itself. The strategy involves stressing the body—by restricting food intake, in this case—to trigger the activation of biological programs in our cells that protect against disease and degeneration.

“Cells and organisms respond adaptively to certain kinds of stress by increasing their ability to cope with more severe stress,” says Mark Mattson, a researcher at the National Institutes of Health’s National Institute on Aging (NIA). “We now have a lot of data pointing to the activation of mechanisms that help cells cope with oxidative stress, maintain their energy levels, and prevent the abnormal accumulation of protein aggregates.”

This makes-me-stronger stress response is often called the “hormesis” effect. Mattson and his colleagues are about to start one of the first clinical trials of a hormesis-based strategy—the “5:2 diet,” a form of intermittent fasting—aimed at slowing age-related cognitive decline.

The pilot study will enroll 20 women between 55 and 70 who are at high risk for Alzheimer’s because they are obese and insulin-resistant and already have cognitive scores in the low normal range. Each will follow the 5:2 intermittent fasting diet for eight weeks—eating her normal diet for five days per week but taking in only 600 calories on the other two (consecutive) days. Mattson’s team will look for changes in each woman’s cognitive ability, cerebrospinal fluid levels of the Alzheimer’s-associated amyloid beta and tau proteins, markers of brain inflammation, and even brain network activity and hippocampus volume.

Eat less, live longer

Hormesis stress-response effects are found throughout biology; probably the best known example is the strengthening of muscles in response to physical exercise. Exercise delivers hormesis-related benefits to aging brains too. But it isn’t the only way to ward off age-related disease, and it might not even be the best. “In laboratory rodents,” says Mattson, “intermittent fasting can increase lifespan by up to 30 percent whereas exercise only increases lifespan by about 5 percent.”

The idea of using dietary restriction to trigger a protective response arose in part from a famous set of experiments in the 1930s [pdf], in which Cornell University researchers determined that a low-calorie diet (with an adequate supply of essential nutrients) could extend dramatically the average lifespan of rats.

In the 1990s, researchers found that calorie restriction also has a striking lifespan-extending effect on other lab animals, including C. elegans roundworms and Drosophila fruit flies. The effect turned out to depend largely on a reduction in activity of a central metabolic hormone, IGF-1 (insulin-like growth factor 1), which controls some aspects of growth and aging.

This suppression of IGF-1 and related insulin signaling is now thought to operate as part of a broad “survive the hardship” program, in which cellular repair and maintenance systems get a general boost. Lifespan extension is the most striking effect seen in animal studies, and there are hints that this might happen even in humans. Other effects seen in animal studies include an increased resistance to cancer, diabetes, neurodegeneration, and strokes. Studies of transgenic “Alzheimer’s mice” on calorie-restricted diets have found, for example, that they are more resistant to amyloid beta overproduction, a process thought to contribute to the disease in humans. Mice that model Parkinson’s and Huntington’s disease also fare better with dietary restriction.

At the brain-cell level, dietary restriction can boost the production of neural growth factors and new memory-related neurons; upregulate neuronal antioxidant systems; ramp up the production of the tiny oxygen-converting energy reactors called mitochondria; reduce inflammation; and increase the production of so-called heat-shock or chaperone proteins, which help prevent amyloid beta and other neurodegeneration-linked proteins from forming abnormal aggregates. Last but not least, dietary restriction can boost the autophagy waste-disposal system, which helps remove such harmful aggregates if they do form.

Remarkably, intermittent fasting (IF) appear to do as well as or better than straight caloric restriction at evoking beneficial hormetic responses, says Mattson—and its fast-then-feast regimen doesn’t necessarily require a reduction in total calories.

What about us primates?

Experiments showing that dietary restriction extends lifespan and delays signs of neurodegeneration come with a major caveat. Most are done in small animals, which evolved to live for only a few months or years—and thus, in principle, have lots of room for improvement. It remains to be seen whether the human brain’s already very long working life of nearly a century can be extended much further by a change in diet.

Only modest support for the notion has come from long-term studies of monkeys on caloric restriction (CR) vs. control diets. “We’ve done some basic behavior testing and we didn’t see any differences between the groups,” says Julie A. Mattison, lead author of an NIA study that followed several dozen rhesus macaques from 1987 until 2011. In that study, monkeys on a 30%-lower-calorie diet on average lived no longer than controls, although there was evidence for a strong protection from cancer when CR was started early in life. In principle, CR’s apparent effect at modestly lowering blood glucose, blood pressure, and inflammation would benefit the brain and help ward off diseases such as Alzheimer’s. But Mattison and her colleagues are only now starting the years-long task of analyzing brain tissue from the monkeys in the study that have already died. She also hopes to do studies in macaques of IF’s effects—effects that may be more evident than CR’s—but these studies are unlikely to look for lifespan-extension outcomes. “It just takes too long,” she says. (Macaques on average live for 27 years in captivity.)

A separate long-term macaque study at the University of Wisconsin-Madison, reported in 2009, did find that a 30% caloric restriction diet extended lifespan compared with a control diet. It also delayed the onset of age-related diseases such as cancers and diabetes, and reduced aging-related brain shrinkage. In a follow-up analysis last year, the Wisconsin researchers reported that elderly monkeys on a CR diet, compared with those on a control diet, showed less age-related iron deposition in key brain regions and better fine-motor control—an effect thought likely to translate into greater resistance to Parkinson’s disease. Similarly, a 2004 NIA study found that six months of a CR-diet gave macaques a greater resistance to a toxin-related brain-cell stress that can cause a form of Parkinson’s.

What, as well as when and how much

The relevance of these monkey studies to humans is somewhat clouded by dietary factors. “We’re finding that the quality of the diet matters a lot,” says Luigi Fontana, a geriatrics and nutrition researcher at Washington University—St. Louis School of Medicine and the University of Salerno in Italy. The Wisconsin monkeys’ diet was processed and high in sucrose whereas the NIA monkeys’ diet was low in sucrose, fat and overall calories, and included more natural, whole-foods—“the Wisconsin diet was more like a modern Western diet and the NIA diet was more like a traditional Mediterranean diet,” Fontana says. Thus the NIA control monkeys already were eating a relatively healthy, low-fat, low-cal diet—“and were living substantially longer than average,” notes Fontana—making it plausible that they would show less benefit from additional calorie restriction. (A healthy Mediterranean diet without CR has a striking disease-preventing effect in humans, and even a 10% CR regimen powerfully extends lifespan in lab rats.)

Fontana notes too that both the NIA and Wisconsin diets were high in protein. He and his colleagues have been finding that reducing protein may be as important as reducing calories in delaying the aging process. “The old dogma is that proteins are safe, and you need them to grow,” he says, adding that proteins may also speed cancer’s growth and the aging process. “We’re starting to study this, and the data are very interesting,” he says.

The main task now, says Fontana, is to understand better how quantity and quality of diet, and other behavioral interventions such as exercise, affect aging and degeneration-related pathways. “Can we find a drug that will mimic the effects of dietary restriction? My answer is no,” he says. “More likely we will be able to find drugs or phytochemicals that can enhance the effects of mild exercise and good-quality calorie-restricted diet—but they will be enhancements, not substitutions.”

Mattson, too, notes that “the changes that occur throughout the body in response to fasting are complex and highly coordinated, so I think it’s unlikely that a pill will elicit all the same effects.” One pill that might be useful, he says, is an appetite suppressant to make it easier for people to eat less when needed. “I can imagine it suppressing appetite for, say, 12-16 hours,” he says, “so that maybe you’d take it before you went to bed at night, and then you wouldn’t be hungry till late afternoon the next day.”